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Controlled bioactive delivery using degradable electroactive polymersAshton, M.D., Cooper, Patricia A., Municoy, S., Desimone, M.F., Cheneler, D., Shnyder, Steven, Hardy, J.G. 18 July 2022 (has links)
Yes / Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries. Here, we report the development of degradable electroactive polymers and their application for the controlled delivery of a clinically relevant drug (the anti-inflammatory dexamethasone phosphate, DMP). Electroactive copolymers composed of blocks of polycaprolactone (PCL) and naturally occurring electroactive pyrrole oligomers (e.g., bilirubin, biliverdin, and hemin) were prepared and solution-processed to produce films (optionally doped with DMP). A combination of in silico/in vitro/in vivo studies demonstrated the cytocompatibility of the polymers. The release of DMP in response to the application of an electrical stimulus was observed to be enhanced by ca. 10-30% relative to the passive release from nonstimulated samples in vitro. Such stimuli-responsive biomaterials have the potential for integration devices capable of delivering a variety of molecules for technical/medical applications. / This research was funded by a variety of sources, and the authors acknowledge the UK Engineering and Physical Sciences Research Council (EPSRC) National Productivity Investment Fund (NPIF) for a PhD Studentship for M.D.A. (Grant references: EP/R512564/1, 2065445), in support of the EPSRC First Grant for J.G.H. (Grant reference: EP/ R003823/1); the UK Royal Society for support of J.G.H. (Grant reference: RG160449); and the UK Royal Society and CONICET (Argentina) for supporting M.D.A., S.M., M.F.D., and J.G.H. (Grant Reference: A103355).
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Advanced Dental Biomaterials: Chemistry, Manipulation and ApplicationsKhurshid, Z., Najeeb, S., Zafar, M.S., Sefat, Farshid 25 February 2021 (has links)
No / Advanced Dental Biomaterials is an invaluable reference for researchers and clinicians within the biomedical industry and academia. The book can be used by both an experienced researcher/clinician learning about other biomaterials or applications that may be applicable to their current research or as a guide for a new entrant into the field who needs to gain an understanding of the primary challenges, opportunities, most relevant biomaterials, and key applications in dentistry.
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Engineering Surface Properties to Modulate Inflammation and Stem Cell Recruitment through Macrophage ActivationHotchkiss, Kelly M 01 January 2018 (has links)
Biomaterials are becoming the most commonly used therapeutic method for treatment of lost or damaged tissue in the body. Metallic materials are chosen for high strength orthopaedic and dental applications. Titanium (Ti) implants are highly successful in young, healthy patients with the ability to fully integrate to surrounding tissue. However the main population requiring these corrective treatments will not be healthy or young, therefore further research into material modifications have been started to improve outcomes in compromised patients. The body’s immune system will generate a response to any implanted material, and control the final outcome. Among the first and most influential, cells to interact with the implant will be macrophages. Throughout this study we have 1) established the ability of macrophages to recognize and differentially activate in response to material surface properties, 2) investigated the role of integrin binding in macrophage activation to material properties, and 3) confirmed the importance of macrophage activation in vivo following Ti implant placement. The generation of a hydrophilic implant surface promoted the greatest anti-inflammatory and pro-regenerative macrophage activation. Surface wettability will control protein adsorption which can activated different integrin binding on macrophages and may be responsible for changes in activation. When integrin β3 subunit binding was prevented hydrophilic surfaces no longer promoted an anti-inflammatory macrophage activation. Additionally, when macrophage levels were reduced using two separate ablation models, MaFIA mice and clodronate liposomes, hydrophilic surfaces no longer promoted anti-inflammatory T-cell populations and cytokine profiles. There were also fewer stem cells adhered to implant surfaces at 1, 3, and 7 days when macrophage populations were compromised.
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Decellularized Matrices Effect on the Adaptive Immune ResponseSowers, Kegan 01 January 2018 (has links)
Decellularized extracellular matrices have been a growing area of interest in the biomedical engineering fields of tissue engineering and regenerative medicine.As these materials move toward clinical applications, the immune response to these materials will be a driving force toward their success in clinical approaches. Fully digested decellularized matrix constructs derived from porcine liver, muscle and lung were created to test the adaptive immune response. Hydrogel characterization ensured that the materials had relatively similar stiffness levels to reduce variability, and in vitro studies were conducted. Each individual construct as well as a gelatin control were plated with a co-culture of macrophages and T-cells to measure T-cell proliferation. In addition standard markers of inflammation through qPCR were measured in the macrophage group. Constructs were then placed into animals for 3 and 7 days in addition to a second group that received constructs for 21 days before secondary constructs were placed. These groups were then sacrificed following 3, 7 and 14 days to measure the residual and memory-like response of the constructs. Our results showed that t-cell proliferation was increased with decellularized constructs, particularly in tissue with higher DNA content. In vivo, animals with secondary treatments showed extended inflammatory response, driven by Th1 and Th17 polarization suggesting a memory-like response due to recognition of peptides in the constructs from secondary placements.
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Study of immune and haemostatic response induced by protein multilayers. / Studie av immunologiska och haemostatiska svar inducerade av proteinmultilager.Richter, Maja January 2010 (has links)
FibMat2.0 is a fibrinogen multilayer developed by AddBIO. Other proteins such as immunoglobulin G (IgG) and human serum albumin (HSA) can also be used to build multilayers with the same technique. The aim of this study of FibMat2.0 was to investigate if the manufacturing of the protein multilayer would induce an immune or haemostatic response in the body. The multilayers of IgG and HSA were also studied. Methods such as null ellipsometry, imaging of coagulation and the cone-and-plate setup were used to study immune reactions, activation of the coagulation cascade, and stability of the multilayers. Small amounts of plasma proteins were adsorbed to fibrinogen multilayers, but complement proteins adsorbed only to the IgG matrix and high molecular weight kininogen (HMWK) adsorbed only to the HSA monolayer. The imaging of coagulation method indicated that the titanium surface and the HSA monolayer activate surface induced coagulation rapidly, whereas fibrinogen and IgG multilayers demonstrated longer coagulation times. Platelets and a few white blood cells were bound to titanium surfaces and fibrinogen multilayers, but not to IgG multilayers or HSA monolayers. A conclusion in this study is that the surface of an implant can be coated with FibMat2.0 without any risks, but more studies are needed to better understand the interactions between the surfaces prepared in the present study and the immune and the haemostatic systems of the human body.
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BIOACTIVE POLY(BETA-AMINO ESTER) BIOMATERIALS FOR TREATMENT OF INFECTION AND OXIDATIVE STRESSLakes, Andrew L. 01 January 2016 (has links)
Polymers have deep roots as drug delivery tools, and are widely used in clinical to private settings. Currently, however, numerous traditional therapies exist which may be improved through use of polymeric biomaterials. Through our work with infectious and oxidative stress disease prevention and treatment, we aimed to develop application driven, enhanced therapies utilizing new classes of polymers synthesized in-house. Applying biodegradable poly(β-amino ester) (PBAE) polymers, covalent-addition of bioactive substrates to these PBAEs avoided certain pitfalls of free-loaded and non-degradable drug delivery systems. Further, through variation of polymer ingredients and conditions, we were able to tune degradation rates, release profiles, cellular toxicity, and material morphology.
Using these fundamentals of covalent drug-addition into biodegradable polymers, we addressed two problems that exist with the treatment of patients with high-risk wound-sites, namely non-biodegradability that require second-surgeries, and free-loaded antibiotic systems where partially degraded materials fall below the minimum inhibitory concentration, allowing biofilm proliferation. Our in situ polymerizable, covalently-bound vancomycin hydrogel provided active antibiotic degradation products and drug release which closely followed the degradation rate over tunable periods.
With applications of antioxidant delivery, we continued with this concept of covalent drug addition and modified a PBAE, utilizing a disulfide moiety to mimic redox processes which glutathione/glutathione disulfide performs. This material was found to not only be hydrolytically biodegradable, but tunable in reducibility through cleavage of the disulfide crosslinker, forming antioxidant groups of bound-thiols, similar to drugs currently used in radioprotective therapies. The differential cellular viability of degradation products containing disulfide or antioxidant thiol forms was profound, and the antioxidant form significantly aided cellular resistance to a superoxide attack, similar to that of a radiation injury.
Pathophysiological oxidation in the form of radiation injury or oxidative stress based diseases are often region specific to the body and thus require specific targeting, and nanomaterials are widely researched to perform this. Utilizing a tertiary-amine base-catalyst, we were able to synthesize a high drug content (20-26 wt%) version of the disulfide PBAE previously unattainable. The reduced version of this material created a linear-chain polymer capable of single-emulsion nanoparticle formulation for use with intravenous antioxidant delivery applications instead of local.
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A Rubric for Electrochemical Testing of Metallic BiomaterialsDe La Fuente, Frederick G 01 August 2014 (has links)
Corrosion is a major factor for the failure of metallic medical implants. Testing a metal’s suseptability to corrosion prior to implantation is key to a successful implantation. Electrochemical processes were used in this study to evaluate the characteristics of corrosion of both AISI 316 stainless steel and titanium alloy Ti6Al4V, welded and non-welded. Linear, potentiodynamic, and cyclic polarization curves were produced by the PARC 2273 potentiostat showing the corrosion tendencies of the metals in four unique solutions 3.5% NaCl, 0.35% NaCl, phosphate buffered saline solution (PBS), and Butterfield phosphate buffered solution (BPS). The concentration of chloride ions in solutions affected the passivation current (Ipassive) and the passivation range of both AISI 316 and Ti6Al4V. In general, larger concentrations of the chloride ions increased the passivation current and decreased the passivation range. Both AISI 316 and Ti6Al4V exhibited passive behavior. Ti6Al4V proved to be the more corrosion resistant metal in the test solutions, showing the ability to repassivate and resist pitting.
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Evaluation of an In Situ Polymerizing Hydrogel Scaffold as a Brain Delivery System for Parkinson’s Disease therapeutics / évaluation d'un échafaudage d'hydrogel polymérisant in situ en tant que système d'administration cérébrale pour les traitements de la maladie de ParkinsonGubinelli, Francesco 10 December 2019 (has links)
La maladie de Parkinson (MP) est la deuxième maladie neurodégénérative la plus répandue. Elle touche 0,3% de la population en général, avec un taux croissant de 1 à 2% chez les personnes de plus de 65 ans. À l’heure actuelle, le seul traitement pharmacologique disponible (L-Dopa) consiste à réduire la sévérité des symptômes moteurs. Plusieurs approches expérimentales sont actuellement à l‘étude pour tenter de ralentir la progression de la maladie, ou réduire à long terme la sévérité des symptômes, mais avec un succès limité.La transplantation cellulaire a déjà montré des effets encourageant dans les modèles animaux et en clinique, mais elle présente également plusieurs limites, notamment la faible survie des cellules greffées, une forte réponse immunitaire conduisant au rejet de la greffe.Les biomatériaux sont des matériaux utilisés et adaptés à des applications médicales. Ils sont conçus pour interagir avec différents systèmes biologiques. Parmi ceux-ci, les hydrogels à base de collagène ont attiré l'attention ces dernières années dans le domaine de la médecine régénérative et de la greffe cellulaire, largement utilisés pour la greffe de peau et la cicatrisation des plaies, la régénération de la moelle épinière, la réparation des os et des tendons. À ce jour, cette approche prometteuse n'a encore été étudiée que très rarement in vivo pour les maladies neurodégénératives telles que la MP. Dans ce travail, nous avons développé un modèle pertinent de la MP pour les rongeurs, capable de montrer une dégénérescence progressive des neurones DA dans la SNpc. En utilisant un vecteur viral adéno-associé (AAV), nous avons surexprimé le domaine C-terminal de la forme LRRK2 mutée (G2019S) avec ou sans α-synucléine mutée (α-synA53T) dans la SNpc. Nos résultats ont montré que, alors que LRRK2G2019S seule ne produisait aucune toxicité, l’α-syn co-exprimé avec LRRK2G2019S produisait une plus grande perte de neurones DA dans la SNpc par rapport à l’α-synA53T seule. La toxicité de l'a-syn est probablement facilitée par l'activité kinase du LRRK2 mutant par le biais d'un mécanisme « cell-autonomous ». Une fois que le modèle neurodégénératif de la maladie de Parkinson a été développé et prêt à tester le potentiel du bio-polymère de collagène en tant que système d'administration, nous avons procédé à la caractérisation de l'échafaud en hydrogel. En utilisant l'imagerie par résonance magnétique (IRM) à champ élevé (11,7 T) et l'analyse histologique, nous avons caractérisé notre hydrogel à base de collagène après polymérisation in vitro et, in vivo, après injection intracérébrale chez le rat. Nos résultats indiquent que les hydrogels à base de collagène peuvent être injectés dans le cerveau sans effets délétères majeurs et que l'IRM est un outil de choix pour le suivi direct et non invasif de la polymérisation et de la greffe d'hydrogel de collagène. L'hydrogel de collagène a montré une réponse immunitaire transitoire et limitée essentiellement localisée autour du site d'injection.Ces résultats suggèrent que notre hydrogel à base de collagène qui polymérise in situ pourrait être utilisé en toute sécurité comme système d'administration intracérébrale de cellules et / ou de molécules trophiques et/ou neuroprotectrices pour la MP. / Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 0.3% of general population, with an increasing rate of 1 to 2% in persons over 65. At the moment the only available pharmacological treatment (L-Dopa) focuses on mitigating symptoms; nowadays treatments to slow down the disease’s progression, or suppress symptoms on the long term remain to be validated.Cellular transplantation had showed encouraging results, but it has some limitation, including the poor survival of the grafted cells, strong immune response and rejection of the graft. Biomaterials are materials used and adapted for medical applications and are designed to interact with different biological systems. Among them, collagen-based hydrogels recently gained attention in the field of regenerative medicine and cellular transplantation, being widely used for skin graft and wound healing, spinal cord regeneration, bones and tendon repair. To date, such promising approach has not been often investigated in vivo for neurodegenerative diseases as PD.In this work we developed a rodent relevant model of PD that is able to show a progressive neurodegeneration of DA neurons in the SNpc. Using adeno-associated viral vector (AAV), we overexpressed the C-terminal domain of mutated LRRK2 form (LRRK2G2019S) with or without mutant α-synuclein (α-synA53T) in the SNpc. Our results showed that, while LRRK2G2019S alone did not produce any toxicity, α-synA53T co-expressed with LRRK2 G2019S produced a greater loss of dopaminergic cells in the SNpc. α-synA53T toxicity is likely to be facilitated by the kinase activity of mutant LRRK2 through a cell autonomous mechanism.Once the neurodegenerative rat model of PD was developed and ready for testing the potential of the collagen scaffold as a delivery system, we proceeded with characterization of the hydrogel scaffold. Using high field (11.7T) magnetic resonance imaging (MRI), and histological analysis we characterized our collagen-based hydrogel after in vitro and, in vivo polymerization after intracerebral injection in rats.Our results indicate that collagen-based hydrogels can be safely injected into the brain without any major adverse effect and that MRI is a tool of choice for a direct and non-invasive in vivo follow-up of collagen hydrogel polymerization and grafting in the brain. The collagen scaffold showed a transitory and limited immune response localized around the site of injection.This results suggest that our in-situ polymerizing collagen-based hydrogel could be safely employed as a delivery system for cells and/or molecules during neuronal transplantation.
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Orthogonal Click Chemistry Hydrogels for Culture and Differentiation of Pluripotent Stem CellsMatthew R Arkenberg (13021746) 08 July 2022 (has links)
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<p>Pluripotent stem cells (PSCs) are increasingly utilized to investigate early human developmental processes including gastrulation and organogenesis of endoderm-derived pancreatic lineages. Critical for tissue development, the PSC niche is a dynamic environment consisting of extracellular matrix (ECM) components that guide cell proliferation, migration, and differentiation. However, investigation of the interplay between the PSC niche and organogenesis has been limited to conventional two-dimensional (2D) cell culture or three-dimensional (3D) platforms requiring use of ill-defined materials (e.g., Matrigel). Furthermore, these systems lack tunability to probe specific qualities of the PSC niche including mechanical properties and biochemical compositions. In this dissertation, modular and dynamic hydrogels were designed to study PSC and niche interactions during differentiation and pancreatic organogenesis. Specifically, two bioorthogonal chemical reactions, thiol-norbornene photopolymerization and tetrazine-norbornene inverse electron demand Diels-Alder (iEDDA) reactions were employed to generate gelatin- and poly(ethylene glycol) (PEG)-based hydrogels with spatiotemporally tunable physicochemical properties. Following mechanical characterization of the hydrogels, the multicomponent gelatin-based hydrogels were assessed for supporting viability and pluripotency of human induced pluripotent stem cells (hiPSCs), as well as for permitting their trilineage differentiation. Next, fully synthetic PEG-based hydrogels with temporally tunable crosslinking density were established to probe the effect of matrix mechanics on definitive endoderm differentiation of the hiPSCs. Finally, hiPSC-to-pancreatic progenitor cell differentiation was explored in both naturally-derived gelatin-based hydrogels and synthetic PEG-based hydrogels, with cells differentiated on a 2D surface as a control. Overall, this work demonstrates that culture dimensionality, material compositions, and mechanics profoundly influence hiPSC differentiation and pancreatic morphogenesis.</p>
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Investigating mucin interactions with diverse surfaces for biomedical applicationsPetrou, Georgia January 2019 (has links)
Mucous membranes are covered with mucus, a viscoelastic hydrogel that plays an essential role in their protection from shear and pathogens. The viscoelasticity of mucus is owing to mucins, a group of densely glycosylated proteins. Mucins can interact with a wide range of surfaces; thus, there is big interest in exploring and manipulating such interactions for biomedical applications. This thesis presents investigations of mucin interactions with hydrophobic surfaces in order to identify the key features of mucin lubricity, as well as describes the development of materials that are optimized to interact with mucins. In Paper I we investigated the domains which make mucins outstanding boundary lubricants. The results showed that the hydrophobic terminal domains of mucins play a crucial role in the adsorption and lubrication on hydrophobic surfaces. Specifically, protease digestion of porcine gastric mucins and salivary mucins resulted in the cleavage of these domains and the loss of lubricity and surface adsorption. However, a “rescue” strategy was successfully carried out by grafting hydrophobic phenyl groups to the digested mucins and enhancing their lubricity. This strategy also enhanced the lubricity of polymers which are otherwise bad lubricants. In Paper II we developed mucoadhesive materials based on genetically engineered partial spider silk proteins. The partial spider silk protein 4RepCT was successfully functionalized with six lysines (pLys-4RepCT), or the Human Galectin-3 Carbohydrate Recognition Domain (hGal3-4RepCT). These strategies were aiming to either non-specific electrostatic interactions between the positive lysines and the negative mucins, or specific binding between the hGal3 and the mucin glycans. Coatings, fibers, meshes and foams were prepared from the new silk proteins, and the adsorption of porcine gastric mucins and bovine submaxillary mucins was measured, demonstrating enhanced adsorption. The work presented demonstrates how mucin-material interactions can provide us with valuable information for the development of new biomaterials. Specifically, mucin-based and mucin-inspired lubricants could provide desired lubrication to a wide range of surfaces, while our new silk based materials could be valuable tools for the development of mucosal dressings. / Slemhinnor täckts av slem, en viskoelastisk hydrogel som spelar en viktig roll för att skydda mot mekanisk nötning och patogener. Muciner, en grupp av tätt glykosylerade proteiner, spelar en viktig roll i viskoelasticiteten av slem. Eftersom muciner kan interagera med diverse ytor är det av stort intresse att utforska och manipulera sådana interaktioner för biomedicinska tillämpningar. Denna avhandling presenterar undersökningar av mucininteraktioner med hydrofoba ytor för att identifiera de viktigaste egenskaperna hos mucinsmörjning, samt beskriver utveckling av material som optimerades för att interagera med muciner. I Artikel I undersökte vi de domäner som bidrar till mucinernas enastående kapacitet som smörjmedel. Resultaten visade att mucinernas hydrofoba terminaldomäner spelar en avgörande roll vid adsorption och smörjning på hydrofoba ytor. Mer specifikt, proteasklyvning av svinmagemuciner och salivmuciner resulterade i klyvningen av dessa domäner och förlust av smörjning och ytadsorption. Genom att länka hydrofobiska fenylgrupper till de uppbrutna mucinerna, lyckades deras smörjningsegenskaper förbättras. Denna strategi förbättrade också smörjningsegenskaper hos andra polymerer som annars har dåliga smörjningsegenskaper. I Artikel II utvecklade vi mukoadhesiva material baserade på genetiskt modifierade partiella spindelsilkeproteiner. Spindelsilkeproteinet 4RepCT funktionaliserades framgångsrikt med tillsats av sex lysiner (pLys-4RepCT), eller den mänskliga Galectin-3 karbohydrat igenkänningsdomänen (hGal3-4RepCT). Syftet med dessa strategier var antingen att öka ospecifika elektrostatiska interaktioner mellan de positiva lysinerna och de negativa mucinerna, eller den specifika bindningen mellan hGal3 och mucin-glykanerna. Beläggningar, fibrer, nät och skum framställdes från de nya silkeproteinerna. Efter att adsorption av svinmagsmuciner och bovina submaxillära muciner uppmätts, visade de nya silkeproteinerna förbättrad mucin adsorption. Detta arbete visar hur interaktioner mellan mucin-material kan bidra med värdefull information för utvecklingen av nya biomaterial. Mucinbaserade och mucininspirerade smörjmedel kan ge önskad smörjning till ett brett spektrum av ytor, medan vår nya silkesbaserad material kan vara ett värdefullt verktyg för utvecklingen av slemhinneförband. / <p>QC 20190412</p>
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